Use of a mixture of sodium hyaluronate and chondroitin sulfate for the treatment of osteoarthritis

ABSTRACT

This invention is related to the use of the composition formed by sodium hyaluronate and sodium chondroitin sulfate for the treatment of chondral lesions in osteoarthritis, and to the use of such composition in the manufacture of a product for such treatment.

This is a U.S. national application under 35 U.S.C. §371 ofPCT/EP02/12703 filed Nov. 13, 2002.

FIELD OF THE INVENTION

This invention is related to methods and compositions for the treatmentof arthritis, and in particular the treatment of osteochondral lesionsassociated with osteoarthritis by means of the intraarticularapplication of a mixture of hyaluronate and chondroitin sulfate.

Specifically, this discovery has its preferred application in thelubrication and regeneration of the articular cartilage damaged by gradeI and grade II osteoarthritis of human or animal (preferably mammalian)joints including without limitation the knee, shoulder, sacroiliac, hip,ankle, elbow, interphalangeal and wrist joints through theintraarticular application of a mixture of sodium hyaluronate andchondroitin sulfate in gel.

The main objectives of the invention are to introduce the new medicaluse of the mixture of sodium hyaluronate and sodium chondroitin sulfatefor the regeneration of articular cartilage damaged by osteoarthritis,corresponding treatment regimens, and the use of the components in themanufacture of products for such therapies.

BACKGROUND OF THE INVENTION

Osteoarthritis is a condition that affects many millions of personsthroughout the world. Previously, there has been no effective treatmentthat specifically targets the chondral lesion associated with thecondition and promotes the in situ regeneration of cartilage at thatsite.

This disease consists of the gradual degeneration and destruction of thearticular cartilage due to traumas, structural deformities of thejoints, and overweight. This process thins the cartilage through aphenomenon called apoptosis, or programed cell death. When the surfacearea has disappeared due to the thinning, it is considered grade Iosteoarthritis; when the tangential surface area has also disappeared,it is characterized as grade II osteoarthritis. There are other levelsof degeneration and destruction, which affect the deep and the calcifiedlayers that border with the subchondral bone.

The clinical manifestations of the development of the condition are:swelling of the joint, pain, crepitation and functional disability that,gradually and steadily, hinders physical mobility, e.g. the taking oflengthy walks and, depending on the affected joint, forced flexion andextension movements. As the condition worsens, pain begins to limit evenminimum efforts and can persist at rest making it difficult to sleep. Ifthe condition persists without correction and/or therapy, the joint istotally destroyed, leading the patient to major replacement surgery withtotal prosthesis, or to disability.

Therapeutic methods for the correction of the articular cartilagelesions that appear during the osteoarthritic disease have beendeveloped, but so far none of them have been able to achieve theregeneration of articular cartilage in situ and in vivo.

The prior art methods include the following:

a) The application of tendinous, periosteal, fascial, muscular orperichondral grafts.

b) The implantation of fibrin or cultured chondrocytes (OsteochondralGrafts Improve Symptoms but May Increase Risk. Of Ostteoarthritis,medscape.com/con/2000/AAOS/story.cfm).

c) The administration of chondrogenic stimulating factors such as“insulin-like growth factors I and TGF-B”.

d) Implantation of synthetic matrices, such as collagen and carbonfiber.

e) Others, such as electromagnetic fields. (J. Buckwalter, M.D., Van C.Mow, Ph. D. and Anthony Ratcliffe, Ph.D. Journal of the American Academyof Orthopaedic Surgery 1994; 2:192-202). All of these have reportedminimal and incomplete results with formation of repair, but notregenerative tissue, resulting in a poor quality tissue that can neithersupport the weighted load nor allow the restoration of an articularfunction with normal movement.

One treatment that has 74% to 90% effectiveness and produces excellentresults, similar to that presented in this invention, is thetransplantation of cultured autologous chondrocytes. This method oftreatment was first reported in 1987 in Sweden and was introduced in1995 to the United States of America. It consists of taking chondralcellular material from the patient, sending it to a laboratory where itis seeded in a proper medium for its proliferation, and then, onceenough volume is achieved (a variable period that may last from weeks tomonths), transporting it in a special container, and finally implantingit in the damaged tissues to cover their defects. This is an expensiveprocedure that requires the patient to be in the operating room for theremoval of the necessary cellular material, and subsequently for theimplantation of the proliferated material. Furthermore, a significantwaiting period is needed for the implant to be ready (VLADIMIR, Bobic,MD AAOS Annual Meeting, Mar. 16, 2000.)

Other, more conventional treatments include antiinflamatories,antirheumatics, systemics, physiotherapy, injection of depot steroidsand, recently, viscoprotection has emerged.

Viscoprotection involves the intraarticular application of commerciallyavailable sodium hyaluronate viscoelastic materials such as HYLAN G-F20, SYNVISC, HYALGAN, ARTZ, etc. The sodium hyaluronate substance doesaffect the rheology of the synovial fluid, producing an almost immediatesensation of free movement and a marked reduction of pain. It has beenproven that the change of the intraarticular fluids attendant to sodiumhyaluronate instillation produces a blockage of the nociceptors ofsubsynovial and capsular tissues and that, in addition to the mechanicalfactors of the osteochondral pathology, the fluids influence thesereceptors with their lubricating properties. Thus the change inviscosity of these fluids acts favorably on the painful osteochondralsymptoms when sodium hyaluronate is instilled. However, the effect ofconventional hyaluronate is temporary because the material remainswithin the articular chamber for only about 72 hours before it isabsorbed and/or metabolized. The residual effects of this substance acton the synovial receptors causing a pain reduction that lasts severalweeks and even months. However, this isolated effect iscounterproductive for the course of the disease and for the viability ofthe cartilage because, as it masks the symptoms, the joint is used withmore intensity and its destruction is accelerated as the originalproblem is not corrected and the damaged articular cartilage is notrestored. Recent studies with a 5 year follow-up with these substancesindicate that clinical improvement is significant and that is representsa remission factor of painful symptoms, but only for short and mediumterm. Also, adverse effects, characterized by severe pain, significantsynovial effusion, rash and ankle edema, have been reported in at least7.2% of the treated patients. In no instance has hyaluronate therapybeen reported to effect cartilage regeneration and long term success.The need exists, therefore, for an improved approach to cartilageregeneration.

As an antecedent to this invention, in 1982, the applicant beganapplying sodium hyaluronate (SH) to thoroughbred race horses atHipódromo de las Américas (Las Américas Race Track), in Mexico City,Mexico. The knees and ankles are the most commonly injured joints inthese horses. Veterinarians at racetracks in the USA had already usedthis procedure, observing the beneficial reaction that this viscoelasticmaterial produced in the injured knees of the horses. The applicantconsidered its use in humans, and conceived of adding some substance tocause the restoration of the damaged surface of the cartilage.

The applicant hypothesized that chondroitin sulfate (CS), the mostimportant part of the aggrecan proteglycans which are the basis ofchondral support, might have a repaving effect.

In 1996 while visiting Alcon Laboratories in Mexico City, the applicantlearned that one of the company's ophthalmic products contained both ofthe above mentioned substances in a gel suspension (VISCOAT®). Theinventor obtained detailed information, including the product monographfor VISCOAT® that states that is has no reported side effects inintroacular use; furthermore, there are ample references from efficacyand safety studies of this product (CILCO, In. Summary of safety andefficacy for Viscoat, 1984). It was then that the applicant decided touse it experimentally in patients with osteoarthritis disorders of alldegrees, and subsequently analyze the results.

The present study reveals another alternative in the management ofosteochondral lesions of the knee through the intraarticular applicationof a mixture of sodium hyaluronate and sodium chondroitin sulfate. Whilebound by no theories, it may be that the remarkable effectiveness ofthis therapy is attributable to the promotion of chondrogenesissynergistically combined with the known benefits of viscoelastictherapy. Implanting an artificial matrix of chondroitin sulfate andsodium hyaluronate may represent an indispensable repair factor, as init naturally arising chondrocytes can proliferate and restore thecontinuity of the tissue, regenerating the destroyed cartilage to itsoriginal form.

With this matrix, the symptomatic evolution is significantly favorableand long lasting due to the regeneration of cartilage at the chondrallesions. No side effect have been reported except in a patient whoreported pain and slight swelling at the site of application, whichsubsided spontaneously in 24 hours; he was given acetaminophen as ananalgesic.

It must be pointed out that in the most preferred usage the product isadministered exactly as it is presented for intraocular use and nochange is made in the formulation. A change in presentation with alarger capacity syringe is now being proposed, as the current ophthalmicpresentation has 0.5 c.c. and 0.75 c.c. syringes.

It must also be pointed out that although this is the same preparationas that used intraocularly, its use for this purpose is totallydifferent as it is applied in a conventional intraaticular manner as aninductor of chondrogenesis, to regenerate the cartilage destroyed byosteoarthritis.

As previously mentioned, experimental application of this composition inhumans started in 1996, and excellent results have been noted. Thesewere confirmed later by arthorscopic studies (direct view of thearticular cartilage through the insertion of a camera into the joint),pathological anatomy and histophysiological studies, all of themconsistent with the clinical findings that the regeneration of normalarticular cartilage was achieved. This is why this treatment ispresented as the only currently available procedure that can offer up to955 regeneration of articular cartilage damaged by grade I and IIosteoarthritis in any joint of the human body.

SUMMARY OF THE INVENTION

This invention was developed to solve the problem of the previouslyavailable techniques related to the treatment of articular cartilagedamaged by osteoarthritis.

This invention introduces a method to achieve regeneration of thearticular cartilage by chondrogenic induction through the intraarticularimplantation of an artificial matrix in patients and animals withchondromalacia and/or osteoarthritis in any joint, but preferably inhuman patients with grade I or II osteoarthritis.

The regeneration process is elicited by implanting an artificial matrixformed by a mixture of chondroitin sulfate and hyaluronic acid orpharmaceutically acceptable salts thereof, where naturally arisingchondrocytes can settle, and where, as they mature, they form, in groupsof 3 or 4, their own definitive hyaline matrix, duplicating the samepattern of the natural cartilage. In this manner the continuity of thearticular surface is recovered, mobility is regained, pain is eliminatedand thus function is recovered.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 to 6 represent pre- and postimplantation arthroscopic imagesfrom patients who underwent the treatment of the present invention:macro and microscopic confirmation of regeneration of the articularsurface with De Novo cartilage with the same characteristics as theoriginal, a conclusive pathology report, and histophysiology tests(S-100 Protein) both of which confirm the characteristics of theregenerated cartilage.

FIGS. 1 and 2 represent pre- and two years posttreatment arthroscopicimages, respectively.

FIG. 3 represents the regeneration of the articular cartilage with DeNovo cartilage.

FIGS. 4 and 5 are microscopic images that show the maturing of the zonetangential of the superficial layer where fully developed and maturingchondrocytes are found, surrounded by a hyaline matrix.

FIG. 6 is a confirmatory histophysiological image with the applicationof S-100 protein. It shows the reaction of the cartilaginous tissue tothis test with a positive result.

FIGS. 7 to 15 show the graphical results of the studies conducted anddescribed herein.

CHARACTERISTICS OF THE PRODUCT

In its preferred embodiment, the chondroitin sulfate/hyaluronatecomposition of the present invention is presented under the trade nameof VISCOAT® (Alcon Laboratories, Inc., Fort Worth, Tex., USA). It isosteoarthritis (OA) in patients, and particularly in those who fail torespond adequately to traditional non-drug therapies and plainanalgesics.

The VISCOAT® product packaging identifies U.S. Pat. Nos. 4,486,416 and6,051,560, the entire contents of both of which are by this referenceincorporated herein. The VISCOAT® product is also registered before theSSA (Mexican Health Secretariat) under registration number Reg SSA Mex.No 0735 C 88.

According to the manufacturer provided product information:

“VISCOAT® Viscoelastic Solution is a sterile, non-pyrogenic,viscoelastic solution of highly purified, non-inflammatory mediummolecular weight sodium chondroitin sulfate and sodium hyaluroante.VISCOAT® is formulated to a viscosity of 40,000±20,000 cps (at shearrate of 2 sec⁻¹, 25° C.). Each 1 mL of VISCOAT® solution contains notmore than 40 mg sodium chondroitin sulfate, 30 mg sodium hyaluronate,0.45 mg monobasic sodium phosphate, monohydrate, 2.00 mg diabasic sodiumphosphate anhydrous, 4.3 mg sodium chloride (with Water For Injection,USP grade, q.s.). The osmolarity of VISCOAT® is 325 mOsM±40 mOsM; the pHis 7.2±0.2.

Sodium chondroitin sulfate and sodium hyaluronate are quite similar inregard to chemical and physical composition, as each occurs as a large,unbranched chain structure of medium to high molecular weight. Thesodium chondroitin sulfate used in the preparation of the VISCOAT®Viscoelastic Solution has a mean molecular weight of approximately22,500 daltons, while the sodium hyaluronate exhibits a molecular weightof over 500,000 daltons.”

This product has a gel presentation that contains a mixture of sodiumhyaluronate and chondroitin sulfate; these substances exist in naturalform in the human body as part of cartilage, synovial membrane,umbilical cord and vitreous humor of the eye.

DETAILED DESCRIPTION OF THE INVENTION

The product is applied or instilled by conventional intraarticularmeans, typically injection, with prior asepsis and antisepsis of theregion. This is typically done in the treatment room of the physician'soffice. The product applied (injected) is called an implant. Aspreviously explained, CS is the most important part of aggrecan, apredominant proteoglycan in articular cartilage. The CS acts with itslong chains inserted in the protein nucleus as a support element of thechondral stroma. It is thus that it serves as an artificial matrix thatsticks to the bed of the lesion, allowing the migrating, unattached,peripheral chondrocytes of the erosion to settle in it. When theymature, the chondrocytes secrete a definitive hyaline matrix thatreplaces the temporary one afforded by the viscoelastic composition(“wet nurse”) and thus it regenerates until it manages to recover theoriginal shape and thickness. This has been verified when, uponperforming controlled post-implant arthroscopy, cartilage regenerationis observed macroscopically. Microscopically, findings of “De Novo”articular cartilage with normal morphological characteristics, as wellas positive histophysiological results to S-100 protein, are reported.

The preferred method for this invention's chondrogenic induction is theintraarticular application of a mixture containing 60 mg of CS and 45 mgof SH in a gel suspension, equivalent to 1.5 c.c. of the formulation,when dealing with large joints, and the preferred application of amixture containing 30 mg of CS and 22.5 of SH in 0.75 cubic centimetersfor smaller joints such as the coxofemoral, ankle or elbow joints. Theinventor has also determined that for even smaller joints such as theinterphalangeal or wrist joints, a mixture containing 20 mg of CS and 15mg of SH in 0.5 cubic centimeters be used. The number and frequency ofadministration of the doses of the composition will be similar to thoseused in conventional viscoprotective therapy regimens, and will beadjusted to suit the needs of the particular patient. Generally, 2 to 6doses are administered over 1 to 3 months. 2-4 doses administered at10-20 day intervals are preferred. Most preferred is a regimen of 3doses at 15 day intervals with subsequent periodic applications every 3,6, 9, or 12 months, depending on the results. This method produces up toa 94.5% regeneration of the articular cartilage destroyed by grade I andII osteroarthritis, according to the results obtained in the study madeon 325 knees and 16 coxofemoral joints.

DETAILED DESCRIPTION OF THE COMPOUND USED IN THE TREATMENT

As mentioned previously, it is important to consider that in the mostpreferred embodiment of the present invention, the product is appliedexactly as it is presented for intraocular use, without any changes inthe formulation, using a syringe of adequate capacity, for example, a21×32 sterile hypodermic needle. Concentrations of the chondroitinsulfate and hyaluronate useful for purposes of the invention, however,may range from about 0.15 to about 50% by weight for each suchcomponent. The molecular weight of the chondroitin sulfate should begreater than about 20,000 daltons, and preferably between about 20,000and 50,000 daltons. The molecular weight of the hyaluronate should be atleast 500,000 daltons and preferably between about 500,000 and 1,000,000daltons.

In the practice of the invention, sodium hyaluronate may be used atconcentrations from about 0.1 g up to about 10 g in 100 ml water attemperatures between about 4° c. and about 37° C. Chondroitin sulfate isalso used at concentrations from about 0.1 g up to about 10 g in 100 mlwater at temperatures between about 4° C. and about 37° C. Otherpharmaceutically acceptable salts, including without limitationmagnesium, calcium and potassium chondroitin sulfates and hyaluronatesare also useful in the practice of the invention. Within the ranges justdescribed, any quantity of chondroitin sulfate can be added to formbinding interaction with hyaluronate and produce physical and flowproperties suitable for intraarticular uses. Adding 12.6 g ofchondroitin sulfate to 10 g sodium hyaluronate in water, the resultingsolution has viscosity of over 1 million centipoises at 25° C. for lowshear rate below 50 sec⁻¹). The preferred ratio of chondroitin sulfateto hyaluronate is about 4:3 by weight. Preferred concentrations rangefrom about 0.1% to about 5.3% by weight for the chondroitin sulfatecomponent and from about 0.1% to about 4.2% by weight for thehyaluronate component.

The preferred aqueous buffer solution used in the practice of theinvention includes monobasic sodium phosphate, dibasic sodium phosphate,and sodium chloride mixed to form an aqueous buffer to maintain pH ofabout 7 to about 8.0 and osmolarity of 300-350 mOsmol/kg. By raising thebuffer concentrations of monobasic sodium phosphate and disbasic sodiumphosphate, the ionic strength of chondroitin sulfate/hyaluronatesolution is increased. The kinetic rate constant of molecule interactionbetween chondroitin sulfate and hyaluronate is increased by raisingionic strength and temperature. This invention comprises concentrationsof dibasic sodium phosphate and monobasic sodium phosphate from 0.1g/100 ml to 5 g/100 ml and pH range of 7.0 to 8.0 at reactiontemperatures between 4° C. and 40° C. The following example shows theeffect of buffer on the viscosity or apparent molecular weight of themixture for 5.3 g CS/4.2 g SH in 100 ml water:

Buffer 1:

Diabasic sodium phosphate: 4.5 mg/ml Sodium dihydrogen phosphatehydrate: 1.5 mg/ml Viscosity of composition of the present invention at1 sec⁻¹ and 25° C. is 68,878 cps.

Buffer 2:

Dibasic sodium phosphate: 7.5 mg/ml Sodium dihydrogen phosphate hydrate:1.0 mg/ml Viscosity of compositions of the present invention at 1 sec⁻¹and 25° C. is 115,011 cps.

In a most preferred formulations, i.e. the VISCOAT® formulation, eachcubic centimeter of the mixture contains 40 mg of chondroitin sulfate(molecular weight of approximately 22,500 daltons), 30 mg of sodiumhyaluronate (molecular weight of approximately 750,000 daltons), 0.45 mgof sodium monobasic monohydrate phosphate, 2 mg of sodium dibasicanhydrous phosphate, 4.3 mg of sodium chloride and water.

TESTS PERFORMED

TYPE OF STUDIES: Prospective, longitudinal and xperimental.

A study was conducted on 210 patients, 325 knees with chondromalacia andgrades I and II osteoarthritis and 16 joints (coxofemoral) with painfularticular symptoms and functional limitation, treated previously in aconventional manner with NSAIDs or with steroid injections; the patientswere refractory to these tretments.

INCLUSION CRITERIA

The inclusion criteria during this study were as follows:

Patients of both sexes with chronic chondral or osteochondral pathologyof the knee and coxofemoral joint up to grade II arthrosis wereincluded, who had no clinical improvement with conventional treatment,no added autoimmune or neoplastic pathologies, of all ages, with priorarthroscopic surgery, without recent management with systemic orarticular steroids or nonsteroidal antiinflammatories (NSAIDs).

EXCLUSION CRITERIA

The following exclusion criteria were adopted: patients with grade IIIor upper gonarthrosis or coxarthosis, recent or current treatment withsystemic or intraarticular steroids, sever deformities and autoimmune orneoplastic pathology.

NON-INCLUSION CRITERIA

Dropping out of treatment, death, change of medical therapy.

The clinical assessment was as follows:

Pain: slight, moderate or sever.

Gait: occasional claudication, assistance with walking stick or crutchesor impossible to walk.

Mobility: complete arches, slight, moderate or severe limitation.

Synovial effusion: minimum, moderate or severe (occasional or constant).(SCRIPPS SCALE FOR SPECIAL SURGERY)

Radiographic Assessment:

Radiographic, changes, articular clamping, chondromalacia andosteoarthritis. Pre- and posttreatment radiographic studies.

Arthroscopic Assessment:

Pre- and posttreatment images.

RESULTS

210 patients were treated; 325 knees (115 bilateral (230 knees) and 95unilateral (95 knees), 144 women (68.5%), 66 men (31.5%), aged 12 to 86years, a mean of 44.2 years, 48 knees were diagnosed withchondromalacia, 40 with grade I osteoarthritis and 237 with grade IIosteoarthritis.

Another 16 patients treated: 16 coxofemoral (hip) joints.

A visual analog clinical scale (SCRIPPS CLINIC FOR SPECIAL SURGERY) wasapplied and, as shown in FIG. 7, 309 knees (95.07%) showed immediatesignificant improvement and satisfactory evolution for up to two yearsof follow-up, 250 knees (83.3%) remained in the same good conditionswithout needing to take any NSAID for up to 50 months of follow up, 32knees (13%) showed moderate pain and 18 cases (6%) showed no short andmedium term improvement. Finally, from 16 osteoarthritis coxofemoral(grades I, II, III and IV) (hip) joints, 14 (87.5%) grade I and IIcoxofemoral joints showed excellent results, and 2 ( 12.5%) grade IIIand IV coxofemoral joints, due to the advanced degree of deterioration,did not obtain any positive results.

None of the patients had any systemic reactions during this treatment:only one patient reported pain and a slight swelling after theimplantation.

FIGS. 8-10 show the previously described results.

To complement the previous results, a comparative study was conducted on20 patients treated with NSAIDs due to grade II knee osteoarthritis and20 patients treated with VISCOAT® for the same reason. The results,after 90 days, were as shown in FIGS. 11 and 12. FIG. 11 shows theresults for pain reduction and FIG. 12 the results for increasedmobility, each after 90 days.

FIG. 13 shows the results after 25 months according to the HSS scale(Scripps Clinics).

DOSES APPLIED

The study continued, as shown in FIG. 14, with the application of 3doses of the composition to 78 knees, which represented 31% of the kneestreated; 151 knees received 2 doses which represented 60.4% and 21 kneesreceived only one dose which represented 8.4%. The 28% shown in thegraph of FIG. 14 corresponds to 70 patients who, after 6 months, neededup to 8 supplementary doses; this has reduced the index of nocturnalpain, gait pain and pain at rest, and increased the range of mobility.

FIG. 15 shows the graphic results of 16 coxofemoral joints, 3 dosescovered 87.5% with excellent results in 14 coxofemoral joints treatedwith the composition, and the 12.5% shown in the graph of FIG. 15corresponds to the 2 patients with grade III and IV osteoarthritis whodid not report any positive results.

These applications were made in 9 male and 7 female patients aged 27 to79 years.

STUDIES AND TESTS PERFORMED ON PATIENTS THAT PROVE CARTILAGEREGENERATION BY THE APPLICATION OF THE COMPOSITION THAT CONTAINS CS ANDSH.

The following examples are given to illustrate and demonstrate the newuse of the composition of this invention.

°69 year old female patient treated previously with the composition ofsodium hyaluronate and chondroitin sulfate. Biopsy of knee cartilage.

MICROSCOPIC DESCRIPTION:

A histological study of knee cartilage was performed. Its microscopicdescription was as follows: the sections present fragments of maturecartilage with islands of chondrocyte arranged regularly in groups of 2to 3, with cohesiveness, and surrounded by a hyaline matrix withoutlaminar fibrosis. The chondrocytes have a round nucleus, clearcytoplasm, and they are morphologically normal and with good maturation.There is no endochondral ossification or dystrophic calcification and,as in the previous example, there is no evidence of malignant neoplasia.

Diagnosis: Biopsy of knee cartilage.

De Novo cartilage formation, morphologically and architecturally normal.

This is confirmed by the image in FIG. 3.

°78-year old female patient treated previously with the compound ofsodium hyaluronate and chondroitin sulfate. Biopsy of the femoralcondylar cartilage.

Microscopic description:

A histologic study was made of several irregular tissue fragments thatjointly measured 0.5 cm; they had a white pearly color, a firmconsistency; they were identified as right and left. Parafin techniqueinclusions were made of them.

Diagnosis: biopsy of femur condylar cartilage.

Fragment of mature cartilage with partial hyalinization. (Withoutevidence of malignant neoplasia). See confirmation in the image of FIG.4.

Discussion of the results obtained

The functional result subsequent to the implantation of the product wasvery satisfactory for most of treated patients. The difference betweenthe plain systemic drug management and the intraarticular application ofthe chondroitin sulfate and sodium hyaluronate implant is very evidentlyin favor of the latter. It must be considered that the plainintraarticular rheological change (viscosity, elasticity and plasticity)reduces the pain and stimulates a synovial response, changing theviscoelastic features of the fluid. However, the basic difference liesin the medium and long term response which may be effected by thechondrogenic induction provoked by CS and, with it, the permanentsolution to the chondral lesion, to the clinical manifestations and thefunctional disability, as well as to the risk of major surgery.

Conclusions:

The treatment of osteochondral lesions with intraarticular sodiumchondroitin sulfate and sodium hyaluronate has proven to have asignificantly favorable clinical response compared with the conventionaltreatment. This response has been confirmed with pre- and posttreatmentarthroscopic imaging, conventional and electron microscope examinationas well as histophysiology testing (POSITIVE S-100 Protein) showing thatthe damaged cartilage is regenerated in a period of about 2 yearsrecovering its normal structure and function. The indications for thechondrogenic induction intraarticular treatment are preferably addressedto patients with chondromalacia and grades I and II osteoarthritis inany joint of the human body.

The original cause of the osteochondral pathology should invariably betreated, as the long-term result of the procedure will depend on that.Prior surgical management, where indicated, through minimal invasivesurgery, is an excellent alternative for the integral management ofosteochondral lesions and their better long-term prognosis.

Similarly, the methods of the present invention may be used inconjunction with other known therapies. For example, the chondroitinsulfate-hyaluronate mixture of the present invention may be administeredto a joint in need thereof in combination with one or more other agentsselected from antiinflammatories, antirheumatics, steroids andchondrogenic stimulating factors, either separately or in a singleformulation.

Therefore, the mixture of sodium hyaluronate and sodium chondroitinsulfate can be used now in defined amounts in a therapeutically usefulmanner for all the characterized pathological conditions by the simpleintrarrticular application route, and the absence of risks of bothcomponents makes this therapy particularly attractive.

As previously discussed, the viscoelastic compositions of the presentinvention are known to have utility in ophthalmic surgery. Those skilledin the viscoelastic arts will appreciate, however, that suchcompositions will have utility beyond ophthalmic and joint therapy asdescribed above. They may be used in a variety of therapies, andespecially in drug delivery, cosmetic surgery and reconstructivesurgery. The compositions of the present invention are well suited fordelivery of anti-fibrotics, antibiotics, steroidal and non-steroidalantiinflammatories, anesthetics, analgesics and other medicaments orgene therapies to diseased or traumatized tissues in need thereof.Cosmetically, there compositions may be injected to reduce wrinkles orto treat varicose veins. For treatment of dermal lines or wrinkles,these compositions may combined with a muscle relaxing agent such asbotulinum toxin type A, commercially available as BOTOX® (Allergan,Inc., Irvine Calif., USA), and injected subdermally in the conventionalmanner. The presently disclosed compositions and methods may also beused in any environment where there is a need for tissue separation orstabilization and the potential exists for complications, typicallypost-surgical, arising from tissue fibrosis and/or adhesions. They willbe particularly useful in nasal, spinal cord, cardiovascular,orthopoedic and orthodontic surgical procedures that would otherwise beprone to such complications.

Those skilled in the art will recognize that the preferred modes may bealtered or amended without straying away from the true spirit and scopeof the invention as defined in the enclosed claims.

1. A therapeutic method for the treatment of a joint exhibitingdegeneration of articular cartilage comprising the intraarticularadministration to said joint of a viscous composition comprising atherapeutically effective amount of a mixture of chondroitin sulfate andhyaluronic acid or pharmaceutically acceptable salts thereof.
 2. Themethod of claim 1, wherein the joint is in a human patient and thedegeneration of the cartilage is caused by chondrmalacia orosteoarthritis of grade I or grade II.
 3. The method of either claim 1or claim 2, wherein the composition comprises a mixture of chondroitinsulfate at a concentration of 0.1 to 50% by weight and sodiumhyaluronate at a concentration of 0.1 to 50% by weight.
 4. The method ofclaim 3, wherein the chondroitin sulfate concentration is from 0.1 to5.3% by weight and the sodium hyaluroante concentration is from 0.1 to4.2% by weight of the composition.
 5. The method of claim 4, wherein thecomposition is a sterile, non-pyrogenic, viscoelastic solutioncomprising a mixture of chondroitin sulfate and sodium hyaluronate in aratio of about 4 parts by weight chondroitin sulfate to about 3 parts byweight sodium hyaluronate.
 6. The method of claim 5, wherein theconcentration of chondroitin sulfate is about 40 mg/ml and theconcentration of sodium hyaluronate is about 30 mg/ml.
 7. The method ofclaim 6, wherein the chondroitin sulfate has a molecular weight of20,000 to 50,000 daltons, the sodium hyaluronate has a molecular weightof 500,000 to 1,000,000 daltons, and the composition has a viscosity of20,000 to 60,000 cps.
 8. The method of claim 1, wherein one or moredoses of between 0.5 and 1.5 cubic centimeters of the viscoelasticcomposition are administered to the affected joint.
 9. The method ofclaim 8, wherein 2 to 6 doses of the viscoelastic composition areadministered over 1 to 3 months.
 10. The method of claim 9, wherein 2 to4 doses of the viscoelastic composition are administered at 10 to 20 dayintervals.
 11. The method of claim 10, wherein 3 doses of theviscoelastic composition are administered at 15 day intervals.
 12. Thetherapeutic method according to claim 8, wherein the joint is a humanjoint selected from the group formed by the following joints: i) knees,shoulders and sacroiliac; ii) coxofemoral, ankles and elbows; and iii)interphalangeal and wrists.
 13. The therapeutic method according toclaim 12, wherein each dose of the viscoelastic composition is 1.5 cubiccentimeters of the composition for the knee, shoulder or sacroiliacjoints.
 14. The therapeutic method according to claim 8, wherein eachdose of the viscoelastic composition is 0.75 cubic centimeters of thecomposition for the coxofemoral, ankle or elbow joints.
 15. Thetherapeutic method according to claim 8, wherein each dose of theviscoelastic composition is 0.5 cubic centimeters of the composition forthe interphalangeal or wrist joints.
 16. A method of repairing orregenerating cartilage in a mammalian joint characterized by cartilagedegeneration or trauma, comprising the intraaticular administration of amixture of chondroitin sulfate and hyaluronic acid or pharmaceuticallyacceptable salts thereof.